Paratuberculosis in sheep and goats.

Paratuberculosis is a chronic insidious, often serious, disease of the global small ruminant industries, mainly causing losses from mortalities and reduced productivity on-farm, interference in trading and, in Australia, profound socio-economic impacts that have periodically compromised harmony of rural communities. The pathogenesis, diagnosis, impacts and disease management options for ovine and caprine paratuberculosis are reviewed, comparing current controls in the extensive management system for sheep in wool flocks in Australia with the semi-intensive system of dairy flocks/herds in Greece. Improved understanding of the immune and cellular profiles of sheep with varying paratuberculosis outcomes and the recognition of the need for prolonged vaccination and biosecurity is considered of relevance to future control strategies. Paratuberculosis in goats is also of global distribution although the prevalence, economic impact and strategic control options are less well recognized, possibly due to the relatively meagre resources available for goat industry research. Although there have been some recent advances, more work is required on developing control strategies for goats, particularly in dairy situations where there is an important need for validation of improved diagnostic assays and the recognition of the potential impacts for vaccination. For all species, a research priority remains the identification of tests that can detect latent and subclinical infections to enhance removal of future sources of infectious material from flocks/herds and the food chain, plus predict the likely outcomes of animals exposed to the organism at an early age. Improving national paratuberculosis control programs should also be a priority to manage disease risk from trade. The importance of strong leadership and communication, building trust within rural communities confused by the difficulties in managing this insidious disease, reflects the importance of change management considerations for animal health authorities. Although concerns of vaccine efficacy, safety and issues with diagnosis and administration persist, vaccination is increasingly recognized as providing a robust strategy for managing paratuberculosis, having made important contributions to the health of Australian sheep and the lives of producers with affected properties, and offering a mechanism to reduce risk of infection entering the food chain in ovine and caprine products.

Resolution of Crohn's disease and complex regional pain syndrome following treatment of paratuberculosis.

A cohort of family members with various chronic diseases including Crohn's disease, asthma, complex regional pain syndrome, hypothyroidism, type 1 diabetes mellitus, and lymphangiomatosis and/or evidence of infection by Mycobacterium avium subsp. paratuberculosis (MAP) are described in this series of case reports. MAP was cultured from the blood of three members affected by the first five diseases and there was accompanying elevated anti-MAP IgG in two members. The patient affected by the sixth disease has a markedly elevated anti-MAP titer. The two patients affected by the first four diseases have been treated with a combination of anti-MAP antibiotics and ultraviolet blood irradiation therapy with resolution of the disease symptomatology and inability to culture MAP in post treatment blood samples. These case reports of patients with MAP infections provide supportive evidence of a pathogenic role of MAP in humans.

Successful treatment of asymptomatic or clinically terminal bovine Mycobacterium avium subspecies paratuberculosis infection (Johne's disease) with the bacterium Dietzia used as a probiotic alone or in combination with dexamethasone: Adaption to chronic human diarrheal diseases.

A naturally occurring gastrointestinal disease, primarily of ruminants (Johne disease), is a chronic debilitating disease that is caused by Mycobacterium avium subspecies paratuberculosis (MAP). MAP infection occurs primarily in utero and in newborns. Outside our Dietzia probiotic treatment, there are no preventive/curative therapies for bovine paratuberculosis. Interestingly, MAP is at the center of controversy as to its role in (cause of) Crohn disease (CD) and more recently, its role in diabetes, ulcerative colitis, and irritable bowel syndrome (IBS); the latter two, like CD, are considered to be a result of chronic intestinal inflammation. Treatments, both conventional and biologic agents, which induce and maintain remission are directed at curtailing processes that are an intricate part of inflammation. Most possess side effects of varying severity, lose therapeutic value, and more importantly, none routinely result in prevention and/or cures. Based on (a) similarities of Johne disease and Crohn disease, (b) a report that Dietzia inhibited growth of MAP under specific culture conditions, and (c) findings that Dietzia when used as a probiotic, (i) was therapeutic for adult bovine paratuberculosis, and (ii) prevented development of disease in MAP-infected calves, the goal of the present investigations was to design protocols that have applicability for IBD patients. Dietzia was found safe for cattle of all ages and for normal and immunodeficient mice. The results strongly warrant clinical evaluation as a probiotic, in combination with/without dexamethasone.

Bayesian semiparametric modeling for stochastic precedence, with applications in epidemiology and survival analysis.

We propose a prior probability model for two distributions that are ordered according to a stochastic precedence constraint, a weaker restriction than the more commonly utilized stochastic order constraint. The modeling approach is based on structured Dirichlet process mixtures of normal distributions. Full inference for functionals of the stochastic precedence constrained mixture distributions is obtained through a Markov chain Monte Carlo posterior simulation method. A motivating application involves study of the discriminatory ability of continuous diagnostic tests in epidemiologic research. Here, stochastic precedence provides a natural restriction for the distributions of test scores corresponding to the non-infected and infected groups. Inference under the model is illustrated with data from a diagnostic test for Johne's disease in dairy cattle. We also apply the methodology to the comparison of survival distributions associated with two distinct conditions, and illustrate with analysis of data on survival time after bone marrow transplantation for treatment of leukemia.

Comparison of ante-mortem assays to assess progression/regression of paratuberculosis in individual dairy animals.

Johne's disease, caused by Mycobacterium avium, subspecies paratuberculosis (MAP) is becoming increasingly widespread on dairy farms worldwide, due in part, to the absence of vaccine/drug or curative modalities.  This spread is of concern since MAP is at the center of a controversy as to its role in Crohn's disease.  None of the methods presently available to define paratuberculosis in cattle have been examined for their ability to assess progression/regression of any treatment or intervention of this disease   The research presented herein, therefore was designed to assess the reliability and accuracy of available ante-mortem assays to predict disease change of individual animals undergoing a probiotic, potentially therapeutic, treatment.  Paratuberculosis positive (n = 75) and negative (n = 10) animals were longitudinally monitored over their natural lifetimes with specific serum antibody and fecal shedding assays, and for development of end-stage clinical disease.  Longitudinal, increasing/decreasing serum ELISA values were associated with, and predictive of, progression/regression of disease.  Changes in fecal shedding and serum AGID were of value at only specific stages.  Documentation that ELISA-positive animals were positive for paratuberculosis was done by a compilation of ELISA-independent assays--succumbing with end-stage clinical disease, autopsy, AGID, and MAP fecal shedding.

Assessment of Dietzia subsp. C79793-74 for treatment of cattle with evidence of paratuberculosis.

The objective of the present investigation was to determine whether the bacterium Dietzia subsp. C79793-74, previously shown to inhibit growth of Mycobacterium subsp. paratuberculosis under in vitro culture conditions, has therapeutic value as a probiotic for adult cattle with paratuberculosis.  Animals were obtained from several herds with evidence of disease based on seropositivity and/or fecal shedding.  Sixty-eight cows with initial evidence of Stage II or III paratuberculosis and 2 with an initial Stage IV disease were evaluated longitudinally.  Animals were either treated daily with variable, disease-dependent doses of Dietzia (n = 48) or left untreated (n = 22).  Clinical aspects of disease (diarrhea, emaciated, cachectic and appetite) were recorded until the animal recovered or required euthanasia due to advanced clinical paratuberculosis or other severe conditions.  Paratuberculosis parameters-antibody serology (ELISA, AGID) and fecal culture-were longitudinally monitored over the lifetime of each animal.  The results indicated that daily treatment with Dietzia was therapeutic for paratuberculosis cows based on: (a) longitudinal decline in ELISA values only occurred in animals that were treated; (b) prolonged survival was dependant upon treatment--the length being directly associated with low initial ELISA values; and (c) treated animals were the only ones cured of disease.  Further investigations are envisaged to determine optimal, long-term dosages that may result in even better therapeutic outcomes as well as to evaluate potential application for therapy of the Johne's disease, human-counterpart, Crohn's disease.

Is Mycobacterium avium subsp. paratuberculosis, the cause of Johne's disease in animals, a good candidate for Crohn's disease in man?

Mycobacterium avium subspecies paratuberculosis (MAP) causes Johne's disease or paratuberculosis, a gastro intestinal inflammatory condition in ruminants and other animals, which is similar to Crohn's disease (CD) that occurs in man. The role of MAP in the causation of CD has been under intense investigation in the last few decades. This review summarizes the status of MAP in animals and the food chain and its association with CD in man.

DNA vaccines against mycobacterial diseases.

Bacteria belonging to the genus Mycobacterium can cause several infectious diseases affecting humans and animals. Here, we reviewed the latest advances in the development of DNA vaccines against TB, Buruli ulcer and Johne's disease. Current understanding of the immunity to the respective causative pathogens indicates that the use of DNA vaccines encoding mycobacterial antigens could lead to efficient vaccination strategies. Moreover, characterization of protective mycobacterial antigens has been greatly facilitated by the analysis of immune responses induced after DNA vaccination. In addition, work aiming at optimizing DNA vaccines against mycobacterial diseases and research related to the controversial development of postexposure and therapeutic DNA vaccines are also discussed.

Short communication: progression of Johne's disease curtailed by a probiotic.

The naturally occurring inflammatory bowel disease Johne's, caused by Mycobacterium avium ssp. paratuberculosis (MAP), has many clinical manifestations in common with the human inflammatory bowel disease Crohn's disease. In addition, both lack preventive and curative therapies. Because a high percentage of Crohn's patients harbor MAP, it is not surprising that MAP is at the center of controversy as to its contribution. Special concern is being raised as to what role, if any, food animals play in transmission of MAP to humans. Because management practices, presently considered the best way to control the spread of MAP, have not and most likely will not eliminate MAP from food animals, other preventive or curative measures are needed. The results presented herein show that a unique bacterium, Dietzia ssp. C79793-74, used as a probiotic, was therapeutic for adult paratuberculosis animals, and resulted in a cure rate of 37.5%.

Johne's disease eradication and control: regulatory implications.

The time has come for the livestock industry and the veterinary profession to take Johne's disease seriously in the United States. The continued spread of the disease with accompanying economic hardship to infected herds and the possibility that M. paratuberculosis may be a food-borne pathogen makes inaction a costly proposition. Efforts have started at the national level with NJWG to have guidelines written for a national control program for Johne's disease. A national control program is desirable because it would provide uniformity to control efforts. Veterinarians and livestock owners should be aware of the effort and let their views be known. In addition, national program guidelines already have been written (see the appendix) to certify test-negative herds for paratuberculosis. States that do not offer the certification program should consider it. A list of test-negative herds for Johne's disease that livestock owners could use to buy low risk animals would be a significant step forward in our efforts to control Johne's disease. Federal regulations concerning Johne's disease are outdated and should be changed to facilitate participation by the livestock industry in a Johne's disease control and eradication program.

Effects of administration of anti-CD4 and anti-CD8 monoclonal antibodies on Mycobacterium paratuberculosis infection in intragastrically challenged mice.

In this study, we examined the roles of CD4+ and CD8+ cells in resistance to experimental paratuberculosis. Mice received purified anti-CD4 or anti-CD8 monoclonal antibodies before intragastric challenge with Mycobacterium paratuberculosis and on a biweekly basis for six months. This resulted in sustained depletion of CD4+ and CD8+ cells as verified by flow cytometry analysis of spleen cells from M. paratuberculosis infected mice. Depletion of CD4+ or CD8+ cells did not enhance fecal shedding of M. paratuberculosis, bacillary multiplication in the liver and ceca, nor histopathologic damage to the intestinal tract, mesenteric lymph nodes, spleen and liver. These data suggest that cells other than CD4+ or CD8+ cells are important for host defense in experimental paratuberculosis.

Effects of dialyzable lymph node extracts on lymphoblast proliferative capacity of blood mononuclear cells in cattle with chronic paratuberculosis.

Dialyzable lymph node extracts (DLE) containing transfer factor prepared from calves sensitized to Mycobacterium paratuberculosis and keyhole-limpet hemocyanin (KLH) were administered to 4 adult cows with chronic paratuberculosis. Cutaneous delayed hypersensitivity, lymphocyte blastogenesis, monocyte migration-inhibition, and lymphoblast proliferative capacity as a reflection of interleukin-2 (IL-2) activity were measured in response to M bovis purified protein derivative, johnin, and KLH before and after treatment with DLE. Change in cutaneous delayed hypersensitivity was not evident after DLE treatment. Alterations in histologic features of pre- and posttreatment sections of ileum and mesenteric lymph nodes were not detected. Lymph node extract treatment significantly (P less than 0.05) increased IL-2 activity and migration-inhibition in response to johnin and KLH in vitro. Treatment had no effect on lymphocyte blastogenesis. The data indicate that cattle with chronic paratuberculosis may benefit from DLE treatment, by virtue of increased IL-2 activity, and that effects of DLE are at least partially mediated by an increase in IL-2 activity.